European Journal of Nutrition

, Volume 56, Issue 2, pp 807–818 | Cite as

A possible role for ghrelin, leptin, brain-derived neurotrophic factor and docosahexaenoic acid in reducing the quality of life of coeliac disease patients following a gluten-free diet

  • Francesco Russo
  • Guglielmina Chimienti
  • Caterina Clemente
  • Carla Ferreri
  • Antonella Orlando
  • Giuseppe Riezzo
Original Contribution



A gluten-free diet (GFD) has been reported to negatively impact the quality of life (QoL) of coeliac disease (CD) patients. The gut–brain axis hormones ghrelin and leptin, with the brain-derived neurotrophic factor (BDNF), may affect QoL of CD patients undergoing GFD. Our aims were to evaluate whether: (a) the circulating concentrations of leptin, ghrelin and BDNF in CD patients were different from those in healthy subjects; (b) GFD might induce changes in their levels; (c) BDNF Val66Met polymorphism variability might affect BDNF levels; and (d) serum BDNF levels were related to dietary docosahexaenoic acid (DHA) as a neurotrophin modulator.


Nineteen adult coeliac patients and 21 healthy controls were included. A QoL questionnaire was administered, and serum concentrations of ghrelin, leptin, BDNF and red blood cell membrane DHA levels were determined at the enrolment and after 1 year of GFD. BDNF Val66Met polymorphism was analysed.


Results from the questionnaire indicated a decline in QoL after GFD. Ghrelin and leptin levels were not significantly different between groups. BDNF levels were significantly (p = 0.0213) lower in patients after GFD (22.0 ± 2.4 ng/ml) compared to controls (31.2 ± 2.2 ng/ml) and patients at diagnosis (25.0 ± 2.5 ng/ml). BDNF levels correlated with DHA levels (p = 0.008, r = 0.341) and the questionnaire total score (p = 0.041, r = 0.334).


Ghrelin and leptin seem to not be associated with changes in QoL of patients undergoing dietetic treatment. In contrast, a link between BDNF reduction and the vulnerability of CD patients to psychological distress could be proposed, with DHA representing a possible intermediate.


BDNF Coeliac disease DHA Gluten-free diet Ghrelin Leptin Psychological distress 



The authors thank Dr. Benedetta D’Attoma and Dr. Manuela Martulli (IRCCS “Saverio de Bellis”) for their precious technical assistance.

Compliance with ethical standards

Conflict of interest

CF discloses her position as partner of Lipinutragen srl. The other authors declare that they have no competing interests.


  1. 1.
    Gujral N, Freeman HJ, Thomson AB (2012) Celiac disease: prevalence, diagnosis, pathogenesis and treatment. World J Gastroenterol (WJG) 18:6036–6059. doi: 10.3748/wjg.v18.i42.6036 CrossRefGoogle Scholar
  2. 2.
    Pascual V, Dieli-Crimi R, Lopez-Palacios N, Bodas A, Medrano LM, Nunez C (2014) Inflammatory bowel disease and celiac disease: overlaps and differences. World J Gastroenterol (WJG) 20:4846–4856. doi: 10.3748/wjg.v20.i17.4846 CrossRefGoogle Scholar
  3. 3.
    Smith DF, Gerdes LU (2012) Meta-analysis on anxiety and depression in adult celiac disease. Acta Psychiatr Scand 125:189–193. doi: 10.1111/j.1600-0447.2011.01795.x CrossRefGoogle Scholar
  4. 4.
    Sainsbury K, Mullan B, Sharpe L (2013) Reduced quality of life in coeliac disease is more strongly associated with depression than gastrointestinal symptoms. J Psychosom Res 75:135–141CrossRefGoogle Scholar
  5. 5.
    Karwautz A, Wagner G, Berger G, Sinnreich U, Grylli V, Huber W-D (2008) Eating pathology in adolescents with celiac disease. Psychosomatics 49:399–406CrossRefGoogle Scholar
  6. 6.
    Barratt SM, Leeds JS, Sanders DS (2011) Quality of life in Coeliac disease is determined by perceived degree of difficulty adhering to a gluten-free diet, not the level of dietary adherence ultimately achieved. J Gastrointestin Liver Dis 20:241–245Google Scholar
  7. 7.
    Samasca G, Sur G, Lupan I, Deleanu D (2014) Gluten-free diet and quality of life in celiac disease. Gastroenterol Hepatol Bed Bench 7:139–143Google Scholar
  8. 8.
    Casellas F, Rodrigo L, Lucendo AJ, Fernandez-Banares F, Molina-Infante J, Vivas S, Rosinach M, Duenas C, Lopez-Vivancos J (2015) Benefit on health-related quality of life of adherence to gluten-free diet in adult patients with celiac disease. Rev Esp Enferm Dig 107:196–201Google Scholar
  9. 9.
    Nachman F, del Campo MP, Gonzalez A, Corzo L, Vazquez H, Sfoggia C, Smecuol E, Sanchez MIP, Niveloni S, Sugai E, Maurino E, Bai JC (2010) Long-term deterioration of quality of life in adult patients with celiac disease is associated with treatment noncompliance. Dig Liver Dis 42:685–691CrossRefGoogle Scholar
  10. 10.
    Hallert C, Granno C, Hulten S, Midhagen G, Strom M, Svensson H, Valdimarsson T (2002) Living with coeliac disease: controlled study of the burden of illness. Scand J Gastroenterol 37:39–42CrossRefGoogle Scholar
  11. 11.
    Usai P, Manca R, Cuomo R, Lai MA, Boi MF (2007) Effect of gluten-free diet and co-morbidity of irritable bowel syndrome-type symptoms on health-related quality of life in adult coeliac patients. Dig Liver Dis 39:824–828. doi: 10.1016/j.dld.2007.05.017 CrossRefGoogle Scholar
  12. 12.
    Papastamataki M, Papassotiriou I, Bartzeliotou A, Vazeou A, Roma E, Chrousos GP, Kanaka-Gantenbein C (2014) Incretins, amylin and other gut-brain axis hormones in children with coeliac disease. Eur J Clin Invest 44:74–82. doi: 10.1111/eci.12193 CrossRefGoogle Scholar
  13. 13.
    Riezzo G, Ferreri C, Orlando A, Martulli M, D’Attoma B, Russo F (2014) Lipidomic analysis of fatty acids in erythrocytes of coeliac patients before and after a gluten-free diet intervention: a comparison with healthy subjects. Br J Nutr 112:1787–1796. doi: 10.1017/S0007114514002815 CrossRefGoogle Scholar
  14. 14.
    Miyazawa D, Yasui Y, Yamada K, Ohara N, Okuyama H (2010) Regional differences of the mouse brain in response to an alpha-linolenic acid-restricted diet: neurotrophin content and protein kinase activity. Life Sci 87:490–494CrossRefGoogle Scholar
  15. 15.
    Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML (2001) Circulating ghrelin levels are decreased in human obesity. Diabetes 50:707–709CrossRefGoogle Scholar
  16. 16.
    Spencer SJ, Xu L, Clarke MA, Lemus M, Reichenbach A, Geenen B, Kozicz T, Andrews ZB (2012) Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress. Biol Psychiatry 72:457–465. doi: 10.1016/j.biopsych.2012.03.010 CrossRefGoogle Scholar
  17. 17.
    Diz-Chaves Y (2011) Ghrelin, appetite regulation, and food reward: interaction with chronic stress. Int J Pept 2011:898450. doi: 10.1155/2011/898450 CrossRefGoogle Scholar
  18. 18.
    Wittekind DA, Kluge M (2015) Ghrelin in psychiatric disorders—a review. Psychoneuroendocrinology 52:176–194. doi: 10.1016/j.psyneuen.2014.11.013 CrossRefGoogle Scholar
  19. 19.
    Friedman JM (2002) The function of leptin in nutrition, weight, and physiology. Nutr Rev 60:S1–S14 (discussion S68–S84, 85-17) CrossRefGoogle Scholar
  20. 20.
    Linkov F, Burke LE, Komaroff M, Edwards RP, Lokshin A, Styn MA, Tseytlin E, Freese KE, Bovbjerg DH (2014) An exploratory investigation of links between changes in adipokines and quality of life in individuals undergoing weight loss interventions: possible implications for cancer research. Gynecol Oncol 133:67–72CrossRefGoogle Scholar
  21. 21.
    Drewnowski A, Evans WJ (2001) Nutrition, physical activity, and quality of life in older adults: summary. J Gerontol Ser A Biol Sci Med Sci 56(2):89–94CrossRefGoogle Scholar
  22. 22.
    Farr OM, Tsoukas MA, Mantzoros CS (2015) Leptin and the brain: influences on brain development, cognitive functioning and psychiatric disorders. Metabolism 64:114–130CrossRefGoogle Scholar
  23. 23.
    Lu X-Y (2007) The leptin hypothesis of depression: a potential link between mood disorders and obesity? Curr Opin Pharmacol 7:648–652CrossRefGoogle Scholar
  24. 24.
    Huang EJ, Reichardt LF (2001) Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 24:677–736CrossRefGoogle Scholar
  25. 25.
    Pan A, Keum N, Okereke OI, Sun Q, Kivimaki M, Rubin RR, Hu FB (2012) Bidirectional association between depression and metabolic syndrome: a systematic review and meta-analysis of epidemiological studies. Diabetes Care 35:1171–1180CrossRefGoogle Scholar
  26. 26.
    Karege F, Schwald M, Cisse M (2002) Postnatal developmental profile of brain-derived neurotrophic factor in rat brain and platelets. Neurosci Lett 328:261–264CrossRefGoogle Scholar
  27. 27.
    Hashimoto K (2010) Brain-derived neurotrophic factor as a biomarker for mood disorders: an historical overview and future directions. Psychiatry Clin Neurosci 64:341–357CrossRefGoogle Scholar
  28. 28.
    Hong C-J, Liou Y-J, Tsai S-J (2011) Effects of BDNF polymorphisms on brain function and behavior in health and disease. Brain Res Bull 86:287–297CrossRefGoogle Scholar
  29. 29.
    Zou Y-F, Wang Y, Liu P, Feng X-L, Wang B-Y, Zang T-H, Yu X, Wei J, Liu Z-C, Liu Y, Tao M, Li H-C, Li K-Q, Hu J, Li M, Zhang K-R, Ye D-Q, Xu X-P (2010) Association of BDNF Val66Met polymorphism with both baseline HRQOL scores and improvement in HRQOL scores in Chinese major depressive patients treated with fluoxetine. Hum Psychopharmacol 25:145–152CrossRefGoogle Scholar
  30. 30.
    Chen C, Bazan NG (2005) Lipid signaling: sleep, synaptic plasticity, and neuroprotection. Prostaglandins Other Lipid Mediat 77:65–76CrossRefGoogle Scholar
  31. 31.
    Boneva NB, Yamashima T (2012) New insights into “GPR40-CREB interaction in adult neurogenesis” specific for primates. Hippocampus 22:896–905CrossRefGoogle Scholar
  32. 32.
    Sprecher H (2000) Metabolism of highly unsaturated n-3 and n-6 fatty acids. Biochim Biophys Acta 1486:219–231CrossRefGoogle Scholar
  33. 33.
    Ferreira CF, Bernardi JR, Bosa VL, Schuch I, Goldani MZ, Kapczinski F, Salum GA, Dalmaz C, Manfro GG, Silveira PP (2014) Correlation between n-3 polyunsaturated fatty acids consumption and BDNF peripheral levels in adolescents. Lipids Health Dis 13:44CrossRefGoogle Scholar
  34. 34.
    Zingone F, Iavarone A, Tortora R, Imperatore N, Pellegrini L, Russo T, Dorn SD, Ciacci C (2013) The Italian translation of the celiac disease-specific quality of life scale in celiac patients on gluten free diet. Dig Liver Dis 45:115–118CrossRefGoogle Scholar
  35. 35.
    Schmulson M, Lee OY, Chang L, Naliboff B, Mayer EA (1999) Symptom differences in moderate to severe IBS patients based on predominant bowel habit. Am J Gastroenterol 94:2929–2935. doi: 10.1111/j.1572-0241.1999.01440.x CrossRefGoogle Scholar
  36. 36.
    Svedlund J, Sjodin I, Dotevall G (1988) GSRS—a clinical rating scale for gastrointestinal symptoms in patients with irritable bowel syndrome and peptic ulcer disease. Dig Dis Sci 33:129–134CrossRefGoogle Scholar
  37. 37.
    El-Salhy M, Hatlebakk JG, Gilja OH, Hausken T (2015) The relation between celiac disease, nonceliac gluten sensitivity and irritable bowel syndrome. Nutr J 14:92CrossRefGoogle Scholar
  38. 38.
    Antonioli DA (2003) Celiac disease: a progress report. Mod Pathol 16:342–346CrossRefGoogle Scholar
  39. 39.
    Russo F, Chimienti G, Clemente C, D’Attoma B, Linsalata M, Orlando A, De Carne M, Cariola F, Semeraro FP, Pepe G, Riezzo G (2013) Adipokine profile in celiac patients: differences in comparison with patients suffering from diarrhea-predominant IBS and healthy subjects. Scand J Gastroenterol 48:1377–1385. doi: 10.3109/00365521.2013.845907 CrossRefGoogle Scholar
  40. 40.
    Gibert A, Espadaler M, Angel Canela M, Sanchez A, Vaque C, Rafecas M (2006) Consumption of gluten-free products: should the threshold value for trace amounts of gluten be at 20, 100 or 200 p.p.m.? Eur J Gastroenterol Hepatol 18:1187–1195CrossRefGoogle Scholar
  41. 41.
    Chen S-P, Fuh J-L, Wang S-J, Tsai S-J, Hong C-J, Yang AC (2011) Brain-derived neurotrophic factor gene Val66Met polymorphism modulates reversible cerebral vasoconstriction syndromes. PLoS ONE 6:e18024CrossRefGoogle Scholar
  42. 42.
    Hallert C, Astrom J, Sedvall G (1982) Psychic disturbances in adult coeliac disease. III. Reduced central monoamine metabolism and signs of depression. Scand J Gastroenterol 17:25–28CrossRefGoogle Scholar
  43. 43.
    Addolorato G, Di Giuda D, De Rossi G, Valenza V, Domenicali M, Caputo F, Gasbarrini A, Capristo E, Gasbarrini G (2004) Regional cerebral hypoperfusion in patients with celiac disease. Am J Med 116:312–317CrossRefGoogle Scholar
  44. 44.
    Ozsoy S, Besirli A, Abdulrezzak U, Basturk M (2014) Serum ghrelin and leptin levels in patients with depression and the effects of treatment. Psychiatry Investig 11:167–172CrossRefGoogle Scholar
  45. 45.
    Cheung CK, Wu JC-Y (2013) Role of ghrelin in the pathophysiology of gastrointestinal disease. Gut Liver 7:505–512CrossRefGoogle Scholar
  46. 46.
    Carvalho AF, Rocha DQC, McIntyre RS, Mesquita LM, Kohler CA, Hyphantis TN, Sales PMG, Machado-Vieira R, Berk M (2014) Adipokines as emerging depression biomarkers: a systematic review and meta-analysis. J Psychiatr Res 59:28–37CrossRefGoogle Scholar
  47. 47.
    Karmiris K, Koutroubakis IE, Kouroumalis EA (2008) Leptin, adiponectin, resistin, and ghrelin–implications for inflammatory bowel disease. Mol Nutr Food Res 52:855–866CrossRefGoogle Scholar
  48. 48.
    Yu Y-B, Zuo X-L, Zhao Q-J, Chen F-X, Yang J, Dong Y-Y, Wang P, Li Y-Q (2012) Brain-derived neurotrophic factor contributes to abdominal pain in irritable bowel syndrome. Gut 61:685–694CrossRefGoogle Scholar
  49. 49.
    Brown GW, Craig TK, Harris TO, Herbert J, Hodgson K, Tansey KE, Uher R (2014) Functional polymorphism in the brain-derived neurotrophic factor gene interacts with stressful life events but not childhood maltreatment in the etiology of depression. Depress Anxiety 31:326–334. doi: 10.1002/da.22221 CrossRefGoogle Scholar
  50. 50.
    Solakivi T, Kaukinen K, Kunnas T, Lehtimaki T, Maki M, Nikkari ST (2009) Serum fatty acid profile in celiac disease patients before and after a gluten-free diet. Scand J Gastroenterol 44:826–830CrossRefGoogle Scholar
  51. 51.
    van Hees NJM, Giltay EJ, Geleijnse JM, Janssen N, van der Does W (2014) DHA serum levels were significantly higher in celiac disease patients compared to healthy controls and were unrelated to depression. PLoS ONE 9:e97778CrossRefGoogle Scholar
  52. 52.
    Balanza-Martinez V, Fries GR, Colpo GD, Silveira PP, Portella AK, Tabares-Seisdedos R, Kapczinski F (2011) Therapeutic use of omega-3 fatty acids in bipolar disorder. Expert Rev Neurother 11:1029–1047CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Francesco Russo
    • 1
  • Guglielmina Chimienti
    • 2
  • Caterina Clemente
    • 1
  • Carla Ferreri
    • 3
  • Antonella Orlando
    • 1
  • Giuseppe Riezzo
    • 1
  1. 1.Laboratory of Nutritional PathophysiologyNational Institute for Digestive Diseases I.R.C.C.S. “Saverio de Bellis”Castellana GrotteItaly
  2. 2.Department of Biosciences, Biotechnology and BiopharmaceuticsUniversity of BariBariItaly
  3. 3.Consiglio Nazionale delle Ricerche (CNR)ISOF Bio Free RadicalsBolognaItaly

Personalised recommendations